Extreme neutrophil granulocytosis in a patient with anaplastic large cell lymphoma of t-cell lineage

APMIS 115: 778–83, 2007
C 2007 The AuthorsPrinted in Denmark . All rights reservedJournal Compilation C 2007 APMISISSN 0903-4641Extreme neutrophil granulocytosis in a patient withanaplastic large cell lymphoma of T-cell lineageCase report
FREDERIK NEESS ENGSIG,1 MICHAEL BOE MØLLER,2 HANS K. HASSELBALCH,3
BASSAM MAHDI4 and NIELS OBEL1
Departments of 1Infectious Diseases, 2Pathology, 3Haematology and
4Radiology, Odense University Hospital, Denmark
Engsig FN, Møller MB, Hasselbalch HK, Mahdi B, Obel N. Extreme neutrophil granulocytosis in apatient with anaplastic large cell lymphoma of T-cell lineage. Case report. 2005;115:778–83.
We describe a 47-year-old male admitted with fever and extreme neutrophil granulocytosis (up to80¿109/L). All microbiology tests and test for autoimmune disease were negative. CT scan showedpulmonary infiltrates bilaterally, mediastinal lymphadenopathy and splenomegaly. Conventional path-ological examination of bone marrow and lymph node biopsies did not demonstrate malignant cellsand inflammatory disease was suspected. The patient died of multiorgan failure 23 days after admis-sion. Autopsy showed neutrophil infiltration of several organs. Immunohistochemistry and cyto-genetics postmortem led to a diagnosis of anaplastic large cell lymphoma (ALCL) of T-cell lineage.Involvement of peripheral blood with leukemoid reaction is a rare manifestation of ALCL. This caseemphasizes the importance of immunophenotyping in unexplained extreme granulocytosis.
Key words: Leukemoid reaction; immunohistochemical staining; ALCL; infection.
Frederik Neess Engsig, Department of Infectious Diseases, Odense University Hospital, Sdr. Boul-evard 29, DK-5000 Odense C, Denmark. e-mail: fren74/gmail.com
Fever and neutrophil granulocytosis are com-
until 2 weeks previously. The patient had been treated
mon findings in patients with severe bacterial
with V-penicillin and doxycycline prior to admission
infection. However, several non-infectious dis-
but with no clinical effect. On admission the patientpresented with bilateral small sore angular lymph
eases may induce these two essential clinical
glands, oral candidiasis, moderate hypoxia and di-
stigmata and therefore the clinician may be pre-
arrhea. Neurological examination was normal. The
sented with a major differential diagnostic chal-
patient had neutrophil leukocytosis (33¿109/L; nor-
lenge. We describe a patient with anaplastic
mal range 3–10¿109/L), increased CRP (530 mg/l;
large cell lymphoma (ALCL) of T-cell lineage
normal range⬍10 mg/ml), and slightly elevated liver
and extreme neutrophil granulocytosis.
enzymes. Bence Jones protein in blood and urine andtests for autoimmune diseases were all negative. Allmicrobiology tests were negative, including HIV,Epstein Barr and cytomegalovirus serology, PCR of
sputum for legionella, mycoplasma and chlamydia,and cultures of bronchoalveolar lavage fluid. CT-scan
A 47-year-old previously healthy male was admitted
of the head and neck showed a left parietal cerebral
with diarrhea, nausea and fever. He had been well
tumor, 2¿2.5 cm, supposedly an oligodendroglioma,which was considered an incidental finding. CT scansof the abdomen and chest showed pulmonary infil-
Received 29 August 2007.
trates bilaterally with small exudates, discrete
Accepted 5 February 2007.
mediastinal lymphadenopathy not suspected of repre-

GRANULOCYTOSIS IN ANAPLASTIC LYMPHOMA
senting malignancy, and splenomegaly. The followingtests initially showed no abnormality: Chest X-ray,direct laryngoscopy, ultrasound of the neck, dentalexamination, echocardiography, ventilation/perfusionscintigraphy and leukocyte scintigraphy. A bloodsmear showed leukemoid reaction, but there was nosuspicion of malignant hematological disease. A bonemarrow biopsy performed after 1 week was hypercel-lular, consistent with inflammation but without signsof hematological malignancy, which is why immuno-histochemistry and cytogenetic tests were not per-formed. Microscopy of pleural fluid showed acuteand chronic inflammatory cells and reactive meso-thelial cells.
The patient developed respiratory insufficiency and
exanthema on the thighs and trunk along with he-morrhagic chemosis. Repeated chest X rays showed
Fig. 1. CT scan of the abdomen 3 weeks after admis-
increasing infiltration in both lungs.
sion, showing––besides liver and spleen enlarge-
Bacterial infection was initially suspected and
ment––lymphadenophathy (indicated by arrow).
treated with intravenous meropenem (1 g TID), cip-roxin (400 mg BID) and capsule fluconazole (50 mgQD), supplemented with clindamycin. In spite of
the results of the cytogenetic analysis, including spec-
antibiotic treatment, leukocyte count rose to 57¿109/
tral karyotyping, of the last ante mortem bone mar-
L. After 9 days, treatment with Solumedrol (1 mg/
row aspiration showed t(2;17)(p23;q23) in 11 of 30
kg) was initiated and the patient responded with im-
metaphases, including a subclone with an additional
proved respiratory function and regression of eye and
t(3,8)(p21;q24) in 2 metaphases. No t(9;22) was iden-
skin symptoms. 3 weeks after admission the patient
was transferred to the intensive care unit. Leukocyte
In the light of these findings, the two bone marrow
count had increased to 80¿109/L. A new bone mar-
biopsies, the clots from the two pleural fluid examina-
row biopsy still showed leukemoid reaction but no
tions and the skin biopsy were reviewed. By conven-
signs of malignancy. Abdominal CT scan showed
tional H&E staining and Giemsa staining both bone
lymphadenopathy and moderate enlargement of the
marrow biopsies were still without morphologically
liver and spleen.
identifiable tumor cells or lymphoid aggregates (Fig.3C). However, immunohistochemical staining showed
The lymphadenopathy on the neck advanced, but
scattered single lymphoma cells positive for CD30
fine-needle aspirations from these glands showed no
and ALK (Fig. 3D). Similarly, single tumor cells were
malignant cells. The patient ultimately developed
identified by CD30 and ALK staining in the pleural
multi-organ failure and died 23 days after admission.
fluids but not in the skin biopsy.
At autopsy the spleen was enlarged (weight 1700
g) with several small infarcts. The lymph nodes weregrossly normal. The lungs were consolidated butwithout overt tumor formation. In the left cerebral
hemisphere a tumor measuring 4¿4.5¿5 cm wasidentified and shown to be a protoplasmic astrocyto-
Primary systemic ALCL is mainly of T-cell lin-
ma. Spleen, lungs, brain, kidneys, heart and bone
eage and characterized by large pleomorphic
marrow were sampled for microscopic analysis.
cells with abundant cytoplasm, expression of
Lungs and spleen were diffusely infiltrated with me-
CD30 and anaplastic lymphoma kinase (ALK).
dium-to-large tumor cells with moderate to abundantcytoplasm (Fig. 2). Focally, the background showed
Translocation t(2;5) is commonly found in pri-
increased neutrophils. The tumor cells expressed
mary systemic subtypes and along with other
CD30, ALK (finely granular cytoplasmic pattern),
translocations associated with the ALK gene. In
CD4, CD2 (weak) and CD25. They failed to express
our patient a variant translocation was found
CD3, CD5, CD8, CD20, CD79a and PAX5.
(t(2;17)), which is observed in about 2–5% of
Similar tumor cells were infiltrating the myocar-
patients with ALCL, giving rise to the particu-
dium, kidneys, bone marrow and brain, including the
lar granular ALK expression pattern. As op-
astrocytoma, as solitary single cells (Fig. 3A). Vascu-lar transsections often showed intravascular ALK-
posed to the indolent and progressive cutaneous
positive tumor cells among the neutrophils (Fig. 3B).
type, systemic ALCL is aggressive and often
A diagnosis of ALK-positive anaplastic large cell
located in extranodal sites such as the lungs and
lymphoma of T-cell lineage was made. Concurrently,
liver (1, 2). The disease infrequently involves pe-

ENGSIG et al.Fig. 2. Microscopic and immunophenotypic findings in the enlarged spleen. (A) The spleen shows a loosestroma with a fibrous quality. Larger atypical lymphoid cells are dispersed in the stroma, ¿200. (B) Theneoplastic cells strongly express CD30 with granular cytoplasmic and Golgi region pattern, ¿200 (insert,¿630). (C) There is strong ALK staining of the lymphoma cells with a granular cytoplasmic pattern. There isno membranous or nuclear staining, ¿200 (insert, ¿1000). (D) The lymphoma cells are also strongly CD25positive, ¿200. (E) The large atypical tumor cells are variably CD4 positive, ¿400. (F) There are a very smallnumber of scattered CD79a-positive small B-lymphocytes, ¿200.

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